Approach of cellular mechanisms of glomerulosclerosis in a model of accelerated aging the obese Zucker rat

With age, the morphological changes which occur in renal glomeruli in the absence of any added pathology are an expansion of the extracellular matrices (ECM)--glomerular basement membrane (GBM) and mesangial matrix--and lesions of focal and segmental glomerular hyalinosis (FSGH). Although the mechanisms involved in these glomerular changes are still unknown, an inflammatory step seems to precede the expansion of the extracellular matrices, but the nature of the cytokines and adhesion molecules has yet to be explored. In order to understand the cellular and molecular events of the FSGH, we used the genetically obese Zucker rat (fa/fa) which develops several early FSGH lesions. We observed that FSGH is the result of a modification of the podocyte: 1) bulging of the podocyte with endocytotic vesicles rich in albumin; 2) detachment from the GBM, collapsing of the capillary loops with a progressive disappearance of capillary cells and formation of hyalin and lipid deposits, synthesis of new ECM components; 3) focal adherence of the GBM and the basement lamina of Bowman's capsule and synthesis of new matrix. The detachment of the podocytes from the GBM appeared to be linked to the disappearance of the alpha 3 beta 1 integrin, major molecule which anchors the epithelial cells to the GBM. By immuno-gold techniques, we showed that the density of alpha 3 moieties significantly diminished when podocytes are spreaded over the GBM. This integrin is probably bound to the laminin in the GBM.